Development of novel agents to combat existing and newly emerging viral diseases continues to be an area of high priority. The benzotriazole and triazole moieties are very important entities in medicinal chemistry and several antiviral compounds are derived from them. There are 5 specific aims of this proposal. The first is to delineate a novel method for the synthesis of hydroxybenzotriazole ethers using a novel mechanistic basis that essentially utilizes the benzotriazole moiety as an electrophile rather than as a nucleophile. The chemistry relies on easily available or prepared alcohols and can be readily applied to chiral alcohols without loss of chirality. In addition, using suitable alcohols acyclic and cyclic nucleoside look-alikes will be synthesized. The wide range of new benzotriazole-based compounds emerging from this will be subjected to antiviral screening. The second aim of the proposal queries the mechanism of this reaction, which is important in order to further exploit the reactivity of the benzotriazole ring system. The third aim is to explore the use of cycloaddition chemistry between arynes and an azido carbasugar analogue to generate benzotriazolyl 5'-nor nucleoside analogues. The fourth aim is to explore a metal catalysis approach that incorporates Pd-catalyzed C-N bond formation and hydroamination, to derive indole-based nucleoside analogues. The currently unknown entities resulting from three of the specific aims will be tested for antiviral activity. The last specific aim is to utilize the mechanistic understanding of copper-catalyzed azide- alkyne ligation chemistry to regiospecifically introduce a deuterium atom at the C-5 position of triazoles in the same step that leads to the formation of the triazole ring. This will completely circumvent the need for metalation of the triazole moiety subsequent to its formation. This methodology is important in the context of the newly emerging concept of heavy atom substituted pharmaceuticals as well as for metabolic studies of pharmacophores. Introduction of a heavy atom into a pharmaceutical agent can potentially provide more efficacious agents due to the inherent differences in the C-H and C-D bond strengths. Overall, the proposal aims to explore currently unknown avenues in the chemistry of benzotriazoles and triazoles, and most developments are expected to have a significant impact in the development and assessment of novel antiviral agents.